Linear geranylphenols are an interesting subclass of secondary metabolites found primarily in marine organisms. They are biosynthesized in a mixed form from the metabolic pathway of shikimic acid and mevalonic acid. The terpene portion may have a length of up to nine isoprene units, which chain originates from the mevalonate biosynthetic pathway while the aromatic portion is derived from the biosynthetic pathway of the shikimic acid. Among marine organisms in which this type of compound has been isolated are brown seaweed (Faulkner, D. J. Natural Product Reports 1986, 3, 1-33; Ochi, M.; Kotsuki, H.; Inoue, S.; Taniguchi, M. Chemistry 1979, 831-832; Capon, R. J.; Ghisalberti, E. L.; Jefferies, P. R. Phytochemistry 1981, 20, 2598-2600; Gerwick, W. H.; Fenical, W. The Journal of Organic Chemistry 1981, 46, 22-27), sponges (Rosa, S. De; Crispino, A., Giulio, A. De Journal of Natural 1995, 58, 1450-1454; Bifulco, G.; Bruno, I.; Minale, L.; Riccio, R.; Debitus, C.; Bourdy, G.; Vassas, A.; Lavayre, J. Journal of Natural Products 1995, 58, 1444-1449), alcyonaceas (Bowden, B. F.; Coll, J. C. Australian Journal of Chemistry 1981, 34, 2677-2681), gorgonaceas (Ravi, B. N.; Wells, R. J. Australian Journal of Chemistry 1982, 35, 105-112), ascidias (Howard, B. M.; Clarkson, K.; Bernstein, R. L. Tetrahedron Letters 1979, 20, 4449-4452; Targett, N. Journal of Natural Products 1984, 1696, 1975-1976; Guella, G.; Mancini, I.; Pietra, F. Helvetica Chimica Acta 1987, 70, 621-626; Faulkner, D. J. Natural product reports 1993, 10, 497-539; Fu, X.; Hossain, M. B.; Helm, D. Van Der; Schmitz, F. J.; Van der Helm, D. Journal of the American Chemical Society 1994, 116, 12125-12126; Fu, X.; Hossain, M. B.; Schmitz, F. J.; Helm, D. Van Der The Journal of Organic Chemistry 1997, 62, 3810-3819). From the brown algae, compounds with chains of the mono-, sesqui- and di-terpene type have been isolated whereas structures with long linear chains have been obtained from sponges.
For this family of compounds, potent biological activities have been reported including anti-inflammatory (Quang, D. N.; Hashimoto, T.; Arakawa, Y.; Kohchi, C.; Nishizawa, T.; Soma, G.-I.; Asakawa, Y. Bioorganic & medicinal chemistry 2006, 14, 164-8; Bauer, J.; Koeberle, A.; Dehm, F.; Pollastro, F.; Appendino, G.; Northoff, H.; Rossi, A.; Sautebin, L.; Werz, O. Biochemical pharmacology 2011, 81, 259-68), antifungal (Danelutte, A. P.; Lago, J. H. G.; Young, M. C. M.; Kato, M. J. Phytochemistry 2003, 64, 555-559), anti-HIV (Manfredi, K. P.; Vallurupalli, V.; Demidova, M.; Kindscher, K.; Pannell, L. K. Phytochemistry 2001, 58, 153-7), antioxidant (Yamaguchi, L. F.; Lago, J. H. G.; Tanizaki, T. M.; Mascio, P. Di; Kato, M. J. Phytochemistry 2006, 67, 1838-43), the most frequent of reported activities being the antineoplastic activity (Han, Q.-B.; Qiao, C.-F.; Song, J.-Z.; Yang, N.-Y.; Cao, X.-W.; Peng, Y.; Yang, D.-J.; Chen, S.-L.; Xu, H.-X. Chemistry & biodiversity 2007, 4, 940-6; Liu, Q.; Shu, X.; Wang, L.; Sun, A.; Liu, J.; Cao, X. Cellular & molecular immunology 2008, 5, 271-8).
Synthesis of Linear Geranylphenols
As we have seen, these compounds, whose structure combines a linear terpene unit with a phenolic portion and which have been isolated from various organisms, have been shown to possess a large number of biological properties. However, the major problem for the study of this group relates to its low yield for obtaining them from natural sources. Clearly this important structural group requires an overall strategy for the preparation of the natural products containing this pharmacophore as well as systems with other aromatic residues (Osorio, M.; Aravena, J.; Vergara, A.; Taborga, L.; Baeza, E.; Catalán, K.; González, C.; Carvajal, M.; Carrasco, H.; Espinoza, L. Molecules (Basel, Switzerland) 2012, 17, 556-70).
The most recurrent of the synthetic strategies used for the preparation of terpenylphenols consists, as a first step, of the separate preparation of the appropriate terpene and aromatic fragments for the synthesis. The second step is crucial to the success of the synthesis and involves coupling of the synthetic terpenyl equivalent to the aromatic nucleus. The most commonly used methods for anchoring the two portions are numbered in the following list:
1. Condensation of the terpene and the phenol (Friedel-Crafts allylation) catalysed by a Brönsted acid.
2. Direct terpenylation with terpenyltrialkyltin in the presence of a Lewis acid
3. Rearrangement of terpenylylether catalysed by a Lewis acid.
4. Nucleophilic substitution of aryllithium derivatives on alkyl halides.
5. Nucleophilic substitution of alkyllithium derivatives on aryl halides.
6. Nucleophilic addition of aryllithium derivatives to carbonyls of the terpenyl unit and subsequent reduction in the presence of a Lewis acid.
7. Condensation of geraniol and hydroquinone (Friedel-Crafts allylation) catalysed by a Lewis acid.
Condensation of Geraniol with Hydroquinone and Phenols (Friedel-Crafts Allylation) Catalysed by a Lewis Acid.
The most common direct geranylation schemes involves “π-excedent” aromatic compounds in a Friedel-Crafts alloy under acidic conditions (Keinan, E.; Eren, D. The Journal of Organic Chemistry 1987, 18, 3872-3875; Syper, L.; Kloc, K.; Mz.xl; lochowski, J. Tetrahedron 1980, 36, 123-129; Eisohly, H. N.; Turner, C. E.; Clark, A. M.; Eisohly, M. A. Journal of Pharmaceutical Sciences 1982, 71, 1319-23). Despite the number of modifications, these approaches are limited by the inherent instability of the allylic alcohol in the acidic conditions employed and undesirable side reactions (Stevens, K L, Jurd, L. Manners, G. Tetrahedron 1972, 28, 1939-1944). However, when acid catalysis, such as the reaction with oxalic acid, is replaced by the Lewis acid BF3.Et2O, reaction yields are considerably increased, in addition to using non-aqueous solvents such as ether, dioxane, CH2Cl2 and CCl4. For this synthesis strategy, yields close to 60% are obtained (Fedorov, S.; Radchenko, O.; Shubina, L. Pharmaceutical 2006, 23, 70-81; Shubina, L. K.; Fedorov, S. N.; Radchenko, O. S.; Balaneva, N. N.; Kolesnikova, S. a.; Dmitrenok, P. S.; Bode, A.; Dong, Z.; Stonik, V. a. Tetrahedron Letters 2005, 46, 559-562). However, in recent publications where this synthetic strategy has been used to couple hydroquinone to geraniol, reaction yields ranges from 28 to 34% (Takenaka, K.; Tanigaki, Y.; Patil, M. L.; Rao, C. V. L.; Takizawa, S.; Suzuki, T.; Sasai, H. Tetrahedron: Asymmetry 2010, 21, 767-770; Baeza, E.; Catalán, K.; Peña-Cortés, H.; Espinoza, L. Quim. Nova 2012, 35, 523-526), on the other hand when coupling 2,4,5-trimethoxyphenol with geraniol a mixture of mono-coupled compounds is obtained with yields ranging from 13 to 15% (Baeza, E.; Catalan, K.; Villena, J.; Carrasco, H.; Cuellar, M.; Espinoza, L. Journal of the Chilean Chemical Society 2012, 57, 1219-1223).
Therefore, there is still a need for a synthesis process for obtaining linear derivative compounds from geranylorcinol with a good yield.